Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([C@@H:19]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:20][Br:21])=[CH:15][C:10]=1[C:11](OC)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([C@@H:19]([O:22][Si:23]([C:26]([CH3:27])([CH3:28])[CH3:29])([CH3:24])[CH3:25])[CH2:20][Br:21])=[CH:15][C:10]=1[CH2:11][OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc([C@H](CBr)O[Si](C)(C)C(C)(C)C)ccc1OCc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c(CO)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 80.2 %

Procedure:
Borane methylsulfide complex (42.4 ml of ˜10M solution, 424 mmol) was added drop wise to a solution of methyl 2-(benzyloxy)-5-((1R)-2-bromo-1-{[tert-butyl(dimethyl) silyl]oxy} ethyl)benzoate (Preparation 21, 91.0 g) in tetrahydrofuran (1600 ml). The resulting mixture was then heated to reflux for 2 hours and then cooled to 0° C. before quenching with methanol (270 ml). The mixture was left to stir at room temperature for 16 hours and then the solvent removed in vacuo. The residue was partitioned between dichloromethane (500 ml) and water (500 ml). The aqueous phase was separated and extracted with more dichloromethane (500 ml) and the combined organic extracts washed with saturated aqueous sodium chloride (500 ml), dried (magnesium sulphate) and the solvent removed in vacuo. The residue was purified by flash column chromatography on silica gel eluting with cyclohexane:ethyl acetate (100:0 changing to 80:20, by volume) to give the title compound (68.7 g) as a colourless oil.
Reaction SMILES: [OH-].[Na+].[CH:3]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:10].[CH2:11]([CH:13]1[O:15][CH2:14]1)Cl>O.C1(C)C=CC=CC=1>[C:4]1([CH3:10])[CH:5]=[CH:6][CH:7]=[C:8]([O:9][CH2:11][CH:13]2[O:15][CH2:14]2)[CH:3]=1
Reactant: Cc1cccc(O)c1
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc(OCC2CO2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
To a solution of 50 g (1.25 mol) of NaOH in 1200 ml H2O was added 108 g (1 mol) of m-cresol freshly distilled and at 15° C. in one lot 117ml (1.5 mol) of epichlorohydrin. The emulsion was stirred at room temperature for 16 hours in a creased flask. The product was taken up in 1000 ml of toluene and washed with 500 ml water. Distillation yielded 135.7 g=82% of product, bp 61° C. (0.05 mm).
Reaction SMILES: [CH2:1]([C:8]1[C:13]([Br:14])=[CH:12][N:11]=[C:10](I)N=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Sn](CCCC)(CCCC)CCCC)[CH:17]=1.[C:35]1(C)C(C)=CC=CC=1>>[CH2:1]([C:8]1[C:13]([Br:14])=[CH:12][N:11]=[C:10]([C:18]2[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=2)[CH:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reactant: Brc1cnc(I)nc1Cc1ccccc1
Reactant: Cc1ccccc1C
Product: Brc1cnc(-c2cccnc2)cc1Cc1ccccc1

Procedure:
A mixture of 440 mg of 4-benzyl-5-bromo-2-iodopyrimidine, 430 mg of (3-pyridyl)tributyltin, 68 mg of tetrakis (triphenylphosphine)palladium(0) and 5 ml of xylene was heated under ref lux for one hour in a nitrogen atmosphere. After cooling as it was, silica gel was added to the reaction solution and the solvent was removed. The residue was subjected to silica gel column chromatography using 30% ethyl acetate/hexane, to give 110 mg of the target compound.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][C:15](=[O:23])[NH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([CH3:13])([CH3:12])[CH3:11].[CH3:24][O:25][C:26]([C:28]1[O:29][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:31][CH:32]=1)=[O:27]>C(Cl)Cl>[CH3:24][O:25][C:26]([C:28]1[O:29][C:30]([S:33]([N:20]2[CH2:21][CH2:22][CH:17]([NH:16][C:15]([O:14][C:10]([CH3:13])([CH3:11])[CH3:12])=[O:23])[CH2:18][CH2:19]2)(=[O:35])=[O:34])=[CH:31][CH:32]=1)=[O:27]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)o1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(S(=O)(=O)N2CCC(NC(=O)OC(C)(C)C)CC2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
Diisopropylethylamine (0.75 ml, 4.45 mmol) was added in one portion to a stirred solution of piperidin-4-yl-carbamic acid tert-butyl ester (0.45 g, 2.26 mmol) in DCM (5 ml) at room temperature. To this mixture was added 5-chlorosulfonyl-furan-2-carboxylic acid methyl ester (0.5 g, 2.26 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time the mixture was diluted with DCM (100 ml) and washed sequentially with HCl (1M solution, 50 ml), NaOH (1M solution, 50 ml) and brine (50 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated. The resulting solid was collected by filtration, washed with diethyl ether and dried under vacuum to give the title compound (0.76 g, 88% yield) as an off-white solid. Tr=1.98 min, m/z (ES+) (M+Na)+ 411.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+].O>CO>[OH:2][CH2:1][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1ccc(CO)cc1
Temperature: 5 °C

Procedure:
A stirred suspension of 4-formylbenzonitrile (10.0 g; 0.0763 moles) in methanol (100 mL) under nitrogen was cooled to 5° C. Sodium borohydride (1.45 g; 0.0382 moles) was added. After 30 minutes the mixture was added to water (300 mL) and extracted with ethyl acetate (4×100 mL). The combined extracts were washed with aqueous sodium chloride solution (50 mL) and dried over sodium sulfate. Following filtration and removal of solvent under vacuum the product, 4-(hydroxymethyl)benzonitrile, (9.44 g; 93%) was obtained as a white solid. 1H NMR (400 MHz) CDCl3 δ 7.61–7.66 (2H, m), 7.45–7.50 (2H, m), 4.78 (2H, d, J=5.5 Hz), 2.27 (1H, t, J=5.5 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C@H:15]1[CH2:17][O:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[O:27])=[CH:21][CH:20]=1)#[N:2].[CH2:36]([NH:38][CH2:39][CH3:40])[CH3:37]>O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C@H:15]([OH:16])[CH2:17][N:38]([CH2:39][CH3:40])[CH2:36][CH3:37])[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)=[O:27])=[CH:21][CH:20]=1)#[N:2]
Reactant: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccnc2cc1OC[C@H]1CO1
Reactant: CCNCC
Solvent: C1CCOC1
Product: CCN(CC)C[C@@H](O)COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)c2cc1C#N
Temperature: 60 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
After dissolving N-(4-(6-cyano-7-((2R)-oxiran-2-yl)methoxy-4-quinolyl)oxyphenyl)-N′-(4-fluorophenyl)urea (200 mg, 0.425 mmol) in tetrahydrofuran (5.0 ml) under a nitrogen atmosphere, diethylamine (1.0 ml) was added and the mixture was stirred overnight at 60° C. The reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (eluent—ethyl acetate:methanol=9:1), the fraction containing the target substance was concentrated, methanol (5 ml) was added for crystallization, and the crystals were filtered out and blow-dried to obtain the title compound (126.4 mg, 0.233 mmol, 54.7%) as light yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.Cl[C:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:13]>C(Cl)Cl>[CH2:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][C:12](=[O:13])[O:14][C:15]3[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=3)=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: Nc1ccc2c(c1)CCC2
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: O=C(Nc1ccc2c(c1)CCC2)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Aminoindan (212 mg, 1.59 mmol) was dissolved in CH2Cl2 (10 mL), p-nitrophenyl chloroformate (417 mg, 2.07 mmol) was added, and the reaction mixture was stirred at rt overnight. The solid was removed by filtration (discarded), and the filtrate was concentrated under reduced pressure. This gave the title compound as a grey solid which was about 50% pure and was used without further purification. LC-MS: RT=9.98 min, [M+H]+=299.1.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:23])[CH2:15][C:16](=[O:22])[C:17]([O:19]CC)=[O:18])=[C:10]([O:24][CH2:25][CH2:26][O:27][CH3:28])[C:9]=1[O:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.CO.[OH-].[Na+]>O>[CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:23])[CH2:15][C:16](=[O:22])[C:17]([OH:19])=[O:18])=[C:10]([O:24][CH2:25][CH2:26][O:27][CH3:28])[C:9]=1[O:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(Cc2ccccc2)c(OC)c1OCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COCCOc1c(C(=O)CC(=O)C(=O)O)ccc(Cc2ccccc2)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 200 mL round bottomed flask with a stirring bar and a nitrogen inlet was added ethyl 4-(benzyl-3-methoxy-2-methoxyethoxyphenyl)-2,4-dioxobutyrate (1.48 g, 3.57 mmol), THF (30 mL), methanol (30 mL), and sodium hydroxide solution (18 mL of a 1 N solution in water, 18 mmol). This mixture was stirred 2 h at ambient temperature. The organic solvents were removed in vacuo and the aqueous residue was diluted with 30 mL of water. This solution was washed with ethyl ether (2×50 mL) then acidified with 1N HCl. This mixture was extracted with ethyl ether (100 mL). The ether solution was washed with water and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo gave a yellow oil. This material was crystallized by dissolving in 1:1 ether-hexane (−5mL) and storing in a freezer over night. The crystalline product was collected by filtration on a frit and dried in vacuo at ambient temperature to give 4-(benzyl-3-methoxy-2-methoxyethoxyphenyl)-2,4-dioxobutyric acid as yellow needles. MP: 83-85° C. Anal. Calc'd for C21H22O7: C, 65.28; H, 5.74; Found: C, 65.28; H, 6.05. 1H NMR (CDCl3): δ3.39 (s, 3H); 3.71 (t, j=4 Hz, 2H); 3.82 (s, 3H); 3.96 (s, 2H); 4.21 (t, j=4 Hz, 2H); 6.90 (d, j=2Hz, 1H); 7.28 (m, 6H); 9.60 (br s, 1H).
Reaction SMILES: [CH2:1]([CH:3]([NH:6][OH:7])[CH2:4][CH3:5])[CH3:2].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[O:17])=[CH:11][CH:10]=1>>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:17])[N:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[OH:7])=[CH:11][CH:10]=1
Reactant: CCC(CC)NO
Reactant: O=C=Nc1ccc(Br)cc1
Product: CCC(CC)N(O)C(=O)Nc1ccc(Br)cc1

Procedure:
Using the method of Compound 39 Part C, N-(1-ethylpropyl)hydroxylamine (2.6 g, 25 mmol) was reacted with 4-bromophenyl isocyanate (5 g, 25 mmol) to provide 2.1 g of the desired product as a solid, m.p. 129°-131° C. Analysis: Calculated for C12H17BrN2O2 : %C, 47.86; %H, 5.69; %N, 9.3; Found: %C, 47.79; %H, 5.54; %N, 9.25.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][C@@H:15]([N:19]([CH3:39])[C:20]3[C:21]4[CH:28]=[CH:27][N:26](S(C5C=CC(C)=CC=5)(=O)=O)[C:22]=4[N:23]=[CH:24][N:25]=3)[CH2:14]2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.O.C([O-])([O-])=O.[K+].[K+]>CO.CCOC(C)=O>[Cl:8][C:6]1[CH:5]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][C@@H:15]([N:19]([CH3:39])[C:20]3[C:21]4[CH:28]=[CH:27][NH:26][C:22]=4[N:23]=[CH:24][N:25]=3)[CH2:14]2)=[O:12])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N(C)[C@@H]4CCCN(C(=O)CNc5cc(Cl)cc(Cl)c5)C4)ncnc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CN(c1ncnc2[nH]ccc12)[C@@H]1CCCN(C(=O)CNc2cc(Cl)cc(Cl)c2)C1
Temperature: 60 °C
Yield: 101.5 %

Procedure:
To a solution of (R)-2-(3,5-dichlorophenylamino)-1-(3-(methyl(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)ethanone (150 mg, 0.25 mmol) in MeOH:H2O (4:1 mL) was added K2CO3 (141 mg, 1.0 mmol) and the reaction mixture was heated to 60° C. for 1 h. The reaction mixture was concentrated in vacuo and the residue obtained was diluted in EtOAc (50 mL). The EtOAc suspension was filtered through celite and the filtrate was then dried over Na2SO4, and concentrated in vacuo to give a residue that was subjected to purification by column chromatography (silica gel, gradient MeOH in DCM) to afford the titled intermediate (110 mg, 50%). 1H NMR (400 MHz, DMSO-d6): δ 11.65 (d, J=11.2 Hz, 1H), 8.10 (d, J=6.4 Hz, 1H), 7.14 (d, J=13.6 Hz, 1H), 6.75 (s, 1H), 6.69 (s, 1H), 6.62 (s, 1H), 6.55 (s, 1H), 6.35 (m, 1H), 4.69 (m, 1H), 4.41 (m, 1H), 3.99 (m, 2H), 3.00 (m, 1H), 2.88 (m, 1H), 2.60 (m, 1H), 2.49 (s, 3H), 1.94-1.80 (m, 2H), 1.65 (m, 1H), 1.49 (m, 1H). LC-MS: m/z [M+1]=455.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:16]([CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[N:15][O:14][N:13]=2)=O)[CH:5]=[CH:6][C:7]=1[F:8].P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:32][OH:33]>C1C=CC=CC=1.CCO.CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:16]([CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[N:15][O:14][N:13]=2)=[N:32][OH:33])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NO
Reactant: O=C(Nc1ccc(F)c(Cl)c1)c1nonc1CCCN1CCOCC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCO
Solvent: CO
Solvent: c1ccccc1
Product: ON=C(Nc1ccc(F)c(Cl)c1)c1nonc1CCCN1CCOCC1
Reaction time: 1 h
Yield: 50 %

Procedure:
N-(3-Chloro-4-fluorophenyl)-4-(3-morpholin-4-ylpropyl)-1,2,5-oxadiazole-3-carboxamide (10.0 mg, 27.1 μmol) was suspended in benzene (0.4 mL) under a nitrogen atmosphere and phosphorus pentachloride (6.2 mg, 29.8 μmol) was added and the solution was heated at reflux for 2.5 h. The reaction was then stripped to dryness in vacuo. The reaction was dissolved in EtOH (0.3 mL) and hydroxylamine (40 μL, 0.7 mmol) (50% solution in water) was added to the reaction. After stirring for 1 h, the reaction solution was diluted with MeOH and purified with preparative LCMS to give product (5.2 mg, 50%). LCMS for C16H20ClFN5O3(M+H)+: m/z=384.1.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13].[I-].[Na+].[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C)C=O>[N:16]([CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: O=c1[nH]c2ccccc2n1CCCl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCn1c(=O)[nH]c2ccccc21
Temperature: 120 °C
Yield: 98.9 %

Procedure:
In 30 ml of dimethylformamide were dissolved 1.5 g of the above 1:1 (approx.) mixture of Compound h and Compound h', 1.5 g (9.9 mmol) of sodium iodide and 5.0 g (76.3 mmol) of sodium azide and the solution was heated at 120° C. for 48 hours. After cooling, the solvent was distilled off and 50 ml of ethyl acetate was added to the residue. The insolubles were filtered off and the filtrate was washed twice with 5% aqueous sodium thiosulfate solution and, then, three times with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to give 1.38 g (98.9%) of 1-(2-azidoethyl)-2,3-dihydro-2-oxo-1H-benzimidazole (Compound i) as light yellow crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[NH:5][C:6]([C:10]2[C:11](C)=[CH:12][C:13](C)=[C:14]([CH:18]=2)[C:15]([OH:17])=[O:16])=[C:7]([CH3:9])[N:8]=1.IC1C=C(C=CC=1)C(O)=O.IC1C(C)=CC(C)=C(C=1)C(O)=O>>[CH3:1][O:2][CH2:3][C:4]1[NH:5][C:6]([C:10]2[CH:18]=[C:14]([CH:13]=[CH:12][CH:11]=2)[C:15]([OH:17])=[O:16])=[C:7]([CH3:9])[N:8]=1
Reactant: COCc1nc(C)c(-c2cc(C(=O)O)c(C)cc2C)[nH]1
Agent: Cc1cc(C)c(C(=O)O)cc1I
Agent: O=C(O)c1cccc(I)c1
Product: COCc1nc(C)c(-c2cccc(C(=O)O)c2)[nH]1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 2.3, except 3-iodobenzoic acid was used in place of 5-iodo-2,4-dimethylbenzoic acid (compound 1.3).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([C:7]2[C:12]([NH2:13])=[N:11][C:10]([N:14]([CH3:16])[CH3:15])=[C:9]([Cl:17])[N:8]=2)[O:4][N:3]=1.[I:18][CH3:19].[Cl-].[Cl-].[Ca+2]>CN(C)C=O>[I-:18].[CH3:19][N+:3]1[O:4][C:5]([C:7]2[C:12]([NH2:13])=[N:11][C:10]([N:14]([CH3:15])[CH3:16])=[C:9]([Cl:17])[N:8]=2)=[N:6][C:2]=1[NH2:1]
Reactant: CI
Reactant: CN(C)c1nc(N)c(-c2nc(N)no2)nc1Cl
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CN(C)c1nc(N)c(-c2nc(N)[n+](C)o2)nc1Cl
Product: [I-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To 2 ml of dry dimethylformamide is added 340 mg (1.33 mmole) of 3-amino-5-(3-amino-5-dimethylamino-6-chloropyrazin-2-yl)-1,2,4-oxadiazole. The resulting yellow solution is treated with 4 ml (64.3 mmole) of iodomethane. The homogeneous reaction mixture is protected from moisture (CaCl2) and allowed to stand at 40° C. overnight. The reaction mixture is cooled to room temperature and filtered to collect the solid which precipitated during the course of the reaction. The solid is washed with ether and air dried to afford 470 mg. (88%) of the title compound in pure form; m.p. 300°. The title compound can be further purified, if desired, by recrystallization from ethanol to give fine, yellow needles.
Reaction SMILES: CO.[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[CH:5]=[C:4]1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[C:22](#[N:25])[CH:23]=[CH2:24].O>O1CCOCC1>[C:22]([CH2:23][CH2:24][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[CH:5]=[C:4]1[C:17]([O:19][CH2:20][CH3:21])=[O:18])#[N:25]
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)[nH]c2c1
Reactant: C=CC#N
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CCC#N)c2c1
Temperature: 55 °C
Reaction time: 18 h
Yield: 95.4 %

Procedure:
A 40% solution of Triton B in methanol (0.50 mL, 1.1 mmol) is added to a suspension of diethyl 1H-indole-2,6-dicarboxylate (Intermediate A, 2.6 g, 10.0 mmol) and acrylonitrile (2.2 mL, 33.4 mmol) in 1,4-dioxane (25 mL). The reaction mixture is warmed to 55° C. for 30 min and then it is stirred at room temperature for 18 h. Water (30 mL) is added and the mixture is extracted with EtOAc. The organic layer is washed with water, brine, dried (Na2SO4) and concentrated to afford the title crude compound (3.0 g, 96%) as a yellow solid which is used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:14])[C:5](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:6]([OH:8])=O.C([O-])([O-])OC.C([O-])(=O)C.[NH4+:24].[CH3:25]O>O>[N+:11]([C:10]1[CH:9]=[C:5]2[C:4](=[CH:3][C:2]=1[Cl:1])[N:14]=[CH:25][NH:24][C:6]2=[O:8])([O-:13])=[O:12]
Reactant: CO
Reactant: [NH4+]
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1C(=O)O
Agent: CC(=O)[O-]
Agent: COC([O-])[O-]
Solvent: O
Product: O=c1[nH]cnc2cc(Cl)c([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
In a 10-mL volume stainless steel pressure-resistant vessel were placed 0.94 g (4.3 mmol) of 4-chloro-5-nitroanthranilic acid, 1.96 g (18.5 mmol) of methyl orthoformate, 1.42 g (18.5 mmol) of ammonium acetate, and 4.0 mL of methanol. The reaction was carried out at 120° C. for 4 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, and 40 mL of water was added to the reaction mixture. The resulting aqueous mixture was stirred for 15 minutes and filtered to give 0.88 g (isolated yield: 90%) of 6-nitro-7-chloroquinazolin-4-one as a yellow crystalline product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].[I:22]Cl>CO.ClCCl>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([I:22])=[C:11]([CH:10]=1)[CH2:12][OH:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cccc(OCc2ccccc2)c1
Reactant: ClI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: OCc1cc(OCc2ccccc2)ccc1I
Reaction time: 1 h
Yield: 71 %

Procedure:
To a well stirred solution of 3-benzyloxybenzyl alcohol (5.5 g, 25.7 mmol) in methanol (100 mL) and sodium hydrogencarbonate (8.4 g, 100 mmol) was added a 1.0 M solution of iodine monochloride in dichloromethane (30 mL) at 0° C. The reaction mixture was brought to room temperature and stirring continued for additional 1 h. The reaction mixture was concentrated and then diluted with dichloromethane (150 mL), washed with 10% aqueous sodium thiosulfate and dried (Na2SO4). The desired compound was purified by flash chromatography (silica) using 20% ethyl acetate in hexane to give 5-benzyloxy-2-iodobenzyl alcohol (6.2 g, 71% yield). The alcohol (4.2 g, 12.4 mmol) was dissolved in dichloromethane (100 mL) added acetic anhydride (2.52 g, 24.7 mmol) and catalytic amount of 4-dimethylaminopyridine. The reaction mixture was then stirred for 12 h, washed with aqueous sodium hydrogencarbonate and then dried (Na2SO4) to give acetic acid 5-benzyloxy-2-iodo-benzyl ester in quantitative yield. MS (ESI) 405 (M+Na); Rf=2.27.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:12])=[CH:8][C:9]=2[Cl:11])[NH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[CH2:18](N(CC)CC)C.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl.C(OCC)(=O)C>[CH2:18]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:12])=[CH:8][C:9]=2[Cl:11])[NH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:25]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:32]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1N
Reactant: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
Dissolve 3-amino-2-carbethoxy-4,6-dichloroindole (7.8 g, 27.8 mmol) in methylene chloride (500 mL) and add triethylamine (4.2 mL, 30 mmol) followed by benzoyl chloride (3.5 mL, 30 mmol). Stir at room temperature overnight. Dilute with ethyl acetate (300 mL), wash with water and separate the organic phase. Dry (MgSO4) and evaporate the solvent in vacuo to give a solid. Recrystallize (ethyl acetate) to give the title compound as off-white needles (7.75 g, 74%).
Reaction SMILES: [N+:1]([C:4]([N+:11]([O-:13])=[O:12])([CH3:10])[CH2:5][O:6][CH2:7][CH:8]=[CH2:9])([O-:3])=[O:2].ClC1C=C(C=CC=1)C(OO)=[O:19]>C(Cl)(Cl)Cl>[CH2:7]([O:6][CH2:5][C:4]([N+:11]([O-:13])=[O:12])([N+:1]([O-:3])=[O:2])[CH3:10])[CH:8]1[O:19][CH2:9]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCOCC(C)([N+](=O)[O-])[N+](=O)[O-]
Solvent: ClC(Cl)Cl
Product: CC(COCC1CO1)([N+](=O)[O-])[N+](=O)[O-]
Temperature: 70 °C
Yield: 63.7 %

Procedure:
A solution of allyl 2,2-dinitropropyl ether (30 g, 160 mmol) in chloroform (50 ml) was added to a mechanically stirred mixture of m-chloroperoxybenzoic acid (35 g, 200 mmol) and chloroform (300 ml). The mixture was refluxed at 70° C. for 6 h under nitrogen. The mixture was cooled with an ice bath for 30 min and filtered. The filtrate was concentrated and additional precipitate was filtered out. The filtrate was diluted with methylene chloride, washed with 10% sodium thiosulfate, saturated sodium bicarbonate, water and dried. Solvent was removed under vacuum. The yellow liquid residue (31 g) was chrornatographed using silica gel and methylene chloride to give 21 g (63% yield) of 2,2-dinitropropyl glycidyl ether: HNMR (CDCl3): 2.19 (s, 3H), 2.57 (d of d, 1H), 2.79 (t, 1H), 3.10 (m, 1H), 3.40 (d of d, 1H), 3.91 (d of d, 1H), 4.35 (AB quartet, 2H) ppm; IR (neat): 3063 (w), 3005 (m), 2927 (m), 1566 (br, vs), 1468 (m), 1443 (m), 1402 (m), 1380 (m), 1329 (s), 1280 (w), 1254 (w), 1232 (w), 1161 (m), 1112 (br, s), 999 (w), 967 (w), 905 (m), 849 (m), 764 (m) cm−1.